Dipartimento di Ingegneria Meccanica e Aerospaziale, Sapienza Università di Roma, Via Eudossiana 18, 00184, Rome, Italy.
Commun Biol. 2022 Feb 24;5(1):165. doi: 10.1038/s42003-022-03074-9.
The elusive activation/deactivation mechanism of hERG is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome. Firstly, the available structural data are integrated by providing a homology model for the closed state of the channel. Secondly, molecular dynamics combined with a network analysis revealed two distinct pathways coupling the voltage sensor domain with the pore domain. Interestingly, some LQTS-related mutations known to impair the activation/deactivation mechanism are distributed along the identified pathways, which thus suggests a microscopic interpretation of their role. Split channels simulations clarify a surprising feature of this channel, which is still able to gate when a cut is introduced between the voltage sensor domain and the neighboring helix S5. In summary, the presented results suggest possible activation/deactivation mechanisms of non-domain-swapped potassium channels that may aid in biomedical applications.
我们研究了 hERG 的激活/失活机制，这是一种电压门控钾通道，与包括长 QT 综合征在内的严重遗传性和药物诱导的心脏通道病有关。首先，通过提供通道关闭状态的同源模型，整合了现有的结构数据。其次，分子动力学结合网络分析揭示了两个将电压传感器域与孔域耦合的不同途径。有趣的是，一些已知会损害激活/失活机制的与长 QT 综合征相关的突变沿着所确定的途径分布，这表明它们的作用有微观解释。分裂通道模拟澄清了这种通道的一个令人惊讶的特征，即当在电压传感器域和相邻的 S5 螺旋之间引入切口时，它仍然能够门控。总之，所提出的结果表明非域交换钾通道的可能激活/失活机制，这可能有助于生物医学应用。
